The figure shows Pittsburgh Compound-B (PiB) positron emission tomography (PET) images from a cognitively normal control, an Alzheimer's disease (AD) patient and a Mild Cognitive Impairment (MCI) patient. The images are not shown in the order listed and are intentionally not labeled to make the point that the presence, amount and regional distribution of fibrillar amyloid-beta (A) deposits in the brain do not always correlate with cognitive function. Postmortem studies have shown this previously, but in vivo amyloid imaging allows us to explore this phenomenon in ways that were not previously possible. Two opposing conclusions can be drawn from this figure: 1) either fibrillar A deposition is not related to the cognitive dysfunction of AD or 2) there are modulators of the effects of fibrillar A deposition on cognition. To fully understand the pathophysiology of AD, we must address the question: Which factors determine the impact of A deposition in a given individual? Two of the most important diseases in the aging brain are AD and vascular disease. Many studies have shown that vascular disease can contribute to MCI and dementia. This Program Project renewal application proposes to take an integrative view on the inter-relationships between these two disorders and to examine how vascular disease may influence the presence and rate of progression of symptoms in individuals who have AD pathology in their brain. Finding the answer to this important question requires a combination of postmortem studies with in vivo studies to measure A and its potential modulators in close temporal proximity to cognitive testing. We have a unique opportunity to perform postmortem analyses of subjects who underwent PiB-PET imaging and detailed clinical evaluation before death. The overall specific aims of this Program Project are to: 1) Determine whether a combination of A and vascular Modulating Variables (both systemic and cerebrovascular) improves the prediction of the Study Outcomes (i.e., cognition, brain metabolism and atrophy) over A measures alone; and 2) Increase our understanding of the neuropathological substrates of PiB retention and the threshold for in vivo detection of A deposition. PUBLIC HEALTH RELEVANCE: The overall significance of the proposed work is that neither A nor vascular status alone can give a full picture of the current state or short-term prognosis of cognition for an individual. However, the information gained from the combination of these two pieces of information is hypothesized to be greater than the sum of the parts. Improved understanding of these two common and important pathologies will help us identify those most at risk for the development or progression of cognitive deficits in the near future. This knowledge will allow us to test the impact of treating either AP or vascular pathologies on cognitive outcomes. REVIEW OF INDIVIDUAL COMPONENTS OF THE PROGRAM PROJECT CORE A: ADMINISTRATIVE CORE; William E. Klunk, Core Leader (CL) DESCRIPTION (provided by applicant): To operate a cohesive, coordinated and effective Program Project, the clinical, research, technology, database/statistics and reporting components of the program require central coordination. The Administrative Core of the Program Project provides the organizational structure and integration of the Program Project Cores and research projects. Another administrative function critical for success is liaison with other research programs on which the Program Project relies for success. In the case of this Program Project, all subjects will be recruited from either the Pittsburgh Alzheimer's Disease Research Center (ADRC) or the University of Pittsburgh Gingko Evaluation of Memory Study (GEMS) program. The Program Project Administrative Core will interface with the Administrative Core of the ADRC, which is now in its 25th year and is a large and smoothly functioning clinical and basic research entity. The ADRC organizational structure serves as a template for our organization of the Program Project administrative core, and use of some ADRC resources at no cost to the Program Project greatly leverages the Program Project operations. Greatly facilitating this interaction is the fact that the PI of this Program Project, Dr. Klunk, is co-Director of the ADRC and the Director of the ADRC, Dr. Lopez, is a Project Leader on this Program Project. Furthermore, Leslie Dunn serves as overall Administrator for both the ADRC and this Program Project and she has been ADRC liaison on the GEMS grant over the past 10 years. The connections of the administration of this Program Project to the ADRC and GEMS will optimize the recruitment and retention of subjects into this Program Project. The specific aims are: 1) Supervision of all Program Project functions; 2) Management of the Program Project budget, including expenditures and allocation of funds according to Program Project priorities; 3) Monitor compliance with Federal and University policies and procedures, such as NIH Public Access Policy, Data Sharing Plan and Human Subjects Research compliance; 4) Administrative oversight of the functioning of the Program Project Database; 5) Liaison with the University of Pittsburgh Alzheimer's Disease Research Center (ADRC) in the Department of Neurology; and 6) Liaison with the University of Pittsburgh Gingko Evaluation of Memory Study (GEMS) staff in the Department of Epidemiology. PUBLIC HEALTH RELEVANCE: The overall goal of this Program Project is to determine to role of vascular factors in modulating the effects of brain A deposition. This information will improve our understanding of the pathophysiology of Alzheimer's disease and clarify treatment approaches. The significance of this Administrative Core to that effort is that the successful attainment of these goals requires a centralized oversight and organization for coordination of the individual efforts of the Cores and Projects in recruitment, data acquisition, data analysis and interpretation as well as for management of budgets and compliance with Federal and University policies